8YEV

Dual-specificity tyrosine phosphorylation-regulated kinase 1A in complex with coumestrol

Summary for 8YEV

• Entry DOI: 10.2210/pdb8yev/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, Coumestrol (3 entities in total)
• Functional Keywords: inhibitor, complex, kinase, hydrolase
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 84587.40

Authors

Lee, C.C.,Hsu, K.C. (deposition date: 2024-02-23, release date: 2025-01-01)

Primary citation

Peng, C.H.,Hwang, T.L.,Hung, S.C.,Tu, H.J.,Tseng, Y.T.,Lin, T.E.,Lee, C.C.,Tseng, Y.C.,Ko, C.Y.,Yen, S.C.,Hsu, K.C.,Pan, S.L.,HuangFu, W.C.
Identification, biological evaluation, and crystallographic analysis of coumestrol as a novel dual-specificity tyrosine-phosphorylation-regulated kinase 1A inhibitor.
Int.J.Biol.Macromol., 282:136860-136860, 2024

PubMed Abstract: Alzheimer's disease (AD) is an irreversible neurodegenerative disease, with tau pathology caused by abnormally activated dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) being one of the culprits. Coumestrol, a phytoestrogen and natural antioxidant found in various plants, has been reported to alleviate AD, but the underlying mechanism remains unclear. We confirmed coumestrol as a novel DYRK1A inhibitor through enzyme-based assays, X-ray crystallography, and cell line experiments. Coumestrol exhibited minimal cytotoxicity at concentrations up to 100 μM in cell types such as N2A and SH-SY5Y and reduced DYRK1A-induced phosphorylated tau protein levels by >50 % at 60 μM. In the tau protein phosphorylation and microtubule assembly assay, coumestrol at 30 μM reduced phosphorylated tau by >50 % and restored the microtubule assembly process. Coumestrol also significantly reduced amyloid-β (Aβ)-induced oxidative stress in microglia at 1 μM. In zebrafish larvae co-overexpressing DYRK1A and tau, coumestrol mitigated neuronal damage and protected motor function at 48 h-postfertilization. Our results suggest that coumestrol has potential therapeutic effects in AD by inhibiting DYRK1A, lowering p-Tau levels, restoring microtubule assembly, and protecting microglia cells from Aβ-induced cell death, providing new insights into the development of coumestrol as a potential AD treatment.

PubMed: 39481728
DOI: 10.1016/j.ijbiomac.2024.136860

Experimental method

X-RAY DIFFRACTION (2.25152331476 Å)